DOCSLIB.ORG

Transcriptomic Effects of Adenosine 2A Receptor Deletion in Healthy and Endotoxemic Murine Myocardium

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Transcriptomic Effects of Adenosine 2A Receptor Deletion in Healthy and Endotoxemic Murine Myocardium Clinical and Translational Science Institute Centers 3-1-2017 Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium Kevin J. Ashton Bond University Melissa E. Reichelt The University of Queensland, Australia S. Jamal Mustafa West Virginia University Bunyen Teng West Virginia University Catherine Ledent Universite Libre de Bruxelles See next page for additional authors Follow this and additional works at: https://researchrepository.wvu.edu/ctsi Part of the Medicine and Health Sciences Commons Digital Commons Citation Ashton, Kevin J.; Reichelt, Melissa E.; Mustafa, S. Jamal; Teng, Bunyen; Ledent, Catherine; Delbridge, Lea M. D.; Hofmann, Polly A.; Morrison, R. Ray; and Headrick, John P., "Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium" (2017). Clinical and Translational Science Institute. 528. https://researchrepository.wvu.edu/ctsi/528 This Article is brought to you for free and open access by the Centers at The Research Repository @ WVU. It has been accepted for inclusion in Clinical and Translational Science Institute by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. Authors Kevin J. Ashton, Melissa E. Reichelt, S. Jamal Mustafa, Bunyen Teng, Catherine Ledent, Lea M. D. Delbridge, Polly A. Hofmann, R. Ray Morrison, and John P. Headrick This article is available at The Research Repository @ WVU: https://researchrepository.wvu.edu/ctsi/528 Purinergic Signalling (2017) 13:27–49 DOI 10.1007/s11302-016-9536-1 ORIGINAL ARTICLE Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium Kevin J. Ashton1 & Melissa E. Reichelt2 & S. Jamal Mustafa3 & Bunyen Teng 3 & Catherine Ledent4 & Lea M. D. Delbridge5 & Polly A. Hofmann 6 & R. Ray Morrison7 & John P. Headrick8 Received: 26 April 2016 /Accepted: 9 September 2016 /Published online: 30 September 2016 # Springer Science+Business Media Dordrecht 2016 Abstract Influences of adenosine 2A receptor (A2AR) activity implicating modified G protein/cAMP/PKA and cGMP/NOS on the cardiac transcriptome and genesis of endotoxemic myo- signalling. Lipopolysaccharide (LPS; 20 mg/kg) challenge for carditis are unclear. We applied transcriptomic profiling (39 K 24 h modified >4100 transcripts in wild-type (WT) myocardium Affymetrix arrays) to identify A2AR-sensitive molecules, re- (≥1.5-fold change, FDR < 1 %); the most induced are Lcn2 vealed by receptor knockout (KO), in healthy and endotoxemic (+590); Saa3 (+516); Serpina3n (+122); Cxcl9 (+101) and hearts. Baseline cardiac function was unaltered and only 37 Cxcl1 (+89) and the most repressed are Car3 (−38); Adipoq A2AR-sensitive genes modified by A2ARKO(≥1.2-fold change, (−17); Atgrl1/Aplnr (−14); H19 (−11) and Itga8 (−8). <5 % FDR); the five most induced are Mtr, Ppbp, Chac1, Ctsk Canonical responses centred on inflammation, immunity, cell and Cnpy2 and the five most repressed are Hp, Yipf4, Acta1, death and remodelling, with pronounced amplification of toll- Cidec and Map3k2. Few canonical paths were impacted, with like receptor (TLR) and underlying JAK-STAT, NFκBand altered Gnb1, Prkar2b, Pde3b and Map3k2 (among others) MAPK pathways, and a ‘cardio-depressant’ profile encompassing suppressed ß-adrenergic, PKA and Ca2+ signal- ling, electromechanical and mitochondrial function (and major Kevin J. Ashton and Melissa E. Reichelt denotes equal first authorship shifts in transcripts impacting function/injury including Lcn2, Electronic supplementary material The online version of this article S100a8/S100a9, Icam1/Vcam and Nox2 induction, and Adipoq, (doi:10.1007/s11302-016-9536-1) contains supplementary material, which is available to authorized users. Igf1 and Aplnr repression). Endotoxemic responses were selec- tively modified by A2AR KO, supporting inflammatory suppres- κ * John P. Headrick sion via A2AR sensitive shifts in regulators of NF B and JAK- [email protected] STAT signalling (IκBζ,IκBα, STAT1, CDKN1a and RRAS2) without impacting the cardio-depressant gene profile. Data indi- 1 Faculty of Health Sciences and Medicine, Bond University, Gold cate A2ARs exert minor effects in un-stressed myocardium and Coast, QLD, Australia selectively suppress NFκB and JAK-STATsignalling and cardiac 2 School of Biomedical Sciences, University of Queensland, injury without influencing cardiac depression in endotoxemia. Brisbane, QLD, Australia 3 Department of Physiology and Pharmacology, West Virginia Keywords Adenosine . Adenosine 2A receptor . University, Morgantown, WV, USA Anti-inflammatory . Cytokines . Endotoxemic myocarditis . 4 Universite Libre de Bruxelles, Brussels, Belgium Gene expression . Inflammation . Microarray . Sepsis 5 Department of Physiology, University of Melbourne, Parkville, VIC, Australia 6 Department of Physiology, University of Tennessee Health Science Introduction Center, Memphis, TN, USA 7 Division of Critical Care Medicine, St. Jude Children’s Research Uncontrolled inflammation with sepsis and the systemic inflam- Hospital, Memphis, TN, USA matory response syndrome induce multiple organ dysfunction, 8 Heart Foundation Research Center, Griffith University, including cardiac abnormalities key to disease progression and Southport, QLD 4217, Australia mortality [1]. Unravelling the complex mechanisms governing 28 Purinergic Signalling (2017) 13:27–49 myocardial injury [1, 2] is not only fundamentally important but [39, 40]. In vivo observations suggest marked expansion of also reveals targets for manipulating outcomes. In this regard, this signalling in intact myocardium [41, 42], contrasting adenosine 2A receptors (A2ARs) may fulfil a broadly suppressive in vitro evidence that cardiomyocyte NFκBandIκBkinase role to limit inflammatory injury in multiple tissues [3–6]and signalling is only transiently LPS responsive [43]. enhance myocardial resistance to ischaemic/hypoxic insult, pre- Importantly, these paths are inhibited by A2ARs in other cells, senting a potentially useful therapeutic target [3, 7]. In heart, this with exogenous agonism decreasing [44, 45]andA2ARKO G protein-coupled receptor (GPCR) influences coronary tone increasing NFκB activity [6]. Nonetheless, these paths can and angiogenesis, cardiac contractility, fibroblast growth and fi- also promote myocardial stress-resistance and survival under brosis and may mediate protection via ischaemic pre- and post- conditions that include inflammatory cytokine challenge conditioning [8–10]. Inflammatory modulation contributes to [46–48]. The molecular underpinnings of endotoxemic myo- this latter cardioprotection [9–11], together with the regulation carditis in vivo warrant further investigation, as do the mech- of myocyte kinase signals to limit oxidative stress, mitochondrial anisms countering this dysfunction (including A2ARactivity). dysfunction and cell death [12–14]. However, impacts of the We thus undertook broad-scale transcriptomic profiling of A2AR on integrated myocardial responses to uncontrolled in- hearts from WTand A2AR KO mice, at baseline and following flammation, and the mechanisms underlying such effects, remain endotoxin challenge: shifts in gene expression can shed light to be elucidated. on both functions of the A2AR, and pathogenesis and modu- While adenosine analogues and A2AR agonists can limit lation of endotoxemic myocarditis. There are no prior analy- endotoxemic or septic injury in lung [15, 16], liver [17], brain ses of transcriptome-wide effects of A2ARactivityinmyocar- [18] and heart [19–21], the roles of intrinsic A2ARactivityare dium, and relatively few of the in situ cardiac response to less clear. Receptor deletion fails to modify inflammatory endotoxemia or sepsis [41, 42, 49]. markers/injury in some studies [22], reportedly worsens endotoxemic injury in heart [23] and lung [15, 24] and im- proves survival in models of polymicrobial sepsis [25, 26]. Materials and methods These divergent outcomes may reflect different cell- and organ-specific effects of A2ARs, for example promoting Animals inflammasome formation and macrophage-dependent injury [27], impairing bacterial clearance [25], while activating car- All animal procedures conformed to the Guide for the Care diac survival signalling and suppressing inflammation [3, 7, and Use of Laboratory Animals published by the NIH (publi- 12–14]. Nonetheless, opposing effects of endogenous vs. ex- cation number 85-25, revised 1996). This project (and proto- ogenous (or amplified endogenous) adenosine are evident cols for care of animals) was approved by the Animal Care within cell types, for example inhibiting vs. promoting vascu- and Use Committees of St. Jude Children’s Research Hospital lar myocyte NOS activation with inflammation [28]. The and the University of Tennessee Health Sciences Center. The chronicity of receptor activation may also be critical to A2AR KO mice and WT littermates were obtained from a sub- tissue-specific responses; while acute or transient increases colony of the original lines generated and characterized by in adenosine levels/receptor activity are generally beneficial Ledent et al. [50]. Analysis of cardiac tissue confirms ablation (improving tissue perfusion, ischemic/hypoxic tolerance and of A2AR transcript without compensatory shifts in other aden- reducing cytokines/inflammation), chronic elevations may be osine receptors (Fig. S1). Mice were bred and maintained on- detrimental, exaggerating fibrotic processes via A2BRs in lung site
Load more

Recommended publications
  • CD40 Signaling Synergizes with TLR-2 in the BCR Independent Activation of Resting B Cells
    CD40 Signaling Synergizes with TLR-2 in the BCR Independent Activation of Resting B Cells Shweta Jain, Sathi Babu Chodisetti, Javed N. Agrewala* Immunology Laboratory, Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh, India Abstract Conventionally, signaling through BCR initiates sequence of events necessary for activation and differentiation of B cells. We report an alternative approach, independent of BCR, for stimulating resting B (RB) cells, by involving TLR-2 and CD40 - molecules crucial for innate and adaptive immunity. CD40 triggering of TLR-2 stimulated RB cells significantly augments their activation, proliferation and differentiation. It also substantially ameliorates the calcium flux, antigen uptake capacity and ability of B cells to activate T cells. The survival of RB cells was improved and it increases the number of cells expressing activation induced deaminase (AID), signifying class switch recombination (CSR). Further, we also observed increased activation rate and decreased threshold period required for optimum stimulation of RB cells. These results corroborate well with microarray gene expression data. This study provides novel insights into coordination between the molecules of innate and adaptive immunity in activating B cells, in a BCR independent manner. This strategy can be exploited to design vaccines to bolster B cell activation and antigen presenting efficiency, leading to faster and better immune response. Citation: Jain S, Chodisetti SB, Agrewala JN (2011) CD40 Signaling Synergizes with TLR-2 in the BCR Independent Activation of Resting B Cells. PLoS ONE 6(6): e20651. doi:10.1371/journal.pone.0020651 Editor: Leonardo A. Sechi, Universita di Sassari, Italy Received April 14, 2011; Accepted May 6, 2011; Published June 2, 2011 Copyright: ß 2011 Jain et al.
    [Show full text]
  • An Overview of the Role of Hdacs in Cancer Immunotherapy
    International Journal of Molecular Sciences Review Immunoepigenetics Combination Therapies: An Overview of the Role of HDACs in Cancer Immunotherapy Debarati Banik, Sara Moufarrij and Alejandro Villagra * Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, 800 22nd St NW, Suite 8880, Washington, DC 20052, USA; [email protected] (D.B.); [email protected] (S.M.) * Correspondence: [email protected]; Tel.: +(202)-994-9547 Received: 22 March 2019; Accepted: 28 April 2019; Published: 7 May 2019 Abstract: Long-standing efforts to identify the multifaceted roles of histone deacetylase inhibitors (HDACis) have positioned these agents as promising drug candidates in combatting cancer, autoimmune, neurodegenerative, and infectious diseases. The same has also encouraged the evaluation of multiple HDACi candidates in preclinical studies in cancer and other diseases as well as the FDA-approval towards clinical use for specific agents. In this review, we have discussed how the efficacy of immunotherapy can be leveraged by combining it with HDACis. We have also included a brief overview of the classification of HDACis as well as their various roles in physiological and pathophysiological scenarios to target key cellular processes promoting the initiation, establishment, and progression of cancer. Given the critical role of the tumor microenvironment (TME) towards the outcome of anticancer therapies, we have also discussed the effect of HDACis on different components of the TME. We then have gradually progressed into examples of specific pan-HDACis, class I HDACi, and selective HDACis that either have been incorporated into clinical trials or show promising preclinical effects for future consideration.
    [Show full text]
  • The Metabolic Regulator Histone Deacetylase 9 Contributes to Glucose Homeostasis
    Page 1 of 53 Diabetes The metabolic regulator histone deacetylase 9 contributes to glucose homeostasis abnormality induced by hepatitis C virus infection Jizheng CHEN2, Ning WANG1, Mei DONG1, Min GUO2, Yang ZHAO3, Zhiyong ZHUO3, Chao ZHANG3, Xiumei CHI4, Yu PAN4, Jing JIANG4, Hong TANG2, Junqi NIU4, Dongliang YANG5, Zhong LI1, Xiao HAN1, Qian WANG1* and Xinwen Chen2 1 Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210029, China 2 State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China 3 Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China 4 Department of Hepatology, The First Hospital of Jilin University, Changchun, 130021, China 5 Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430074, China 1 Diabetes Publish Ahead of Print, published online September 29, 2015 Diabetes Page 2 of 53 *Correspondence: Qian WANG, Ph.D. Jiangsu Province Key Lab of Human Functional Genomics Department of Biochemistry and Molecular Biology Nanjing Medical University Nanjing 210029, China E-mail: [email protected] Fax: +86-25-8362 1065 Tel: +86-25-8686 2729 2 Page 3 of 53 Diabetes ABSTRACT Class IIa histone deacetylases (HDACs), such as HDAC4, HDAC5, and HDAC7 provide critical mechanisms for regulating glucose homeostasis. Here we report HDAC9, another class IIa HDAC, regulates hepatic gluconeogenesis via deacetylation of a Forkhead box O (FoxO) family transcription factor, FoxO1, together with HDAC3. Specifically, HDAC9 expression can be strongly induced upon hepatitis C virus (HCV) infection.
    [Show full text]
  • (P -Value<0.05, Fold Change≥1.4), 4 Vs. 0 Gy Irradiation
    Table S1: Significant differentially expressed genes (P -Value<0.05, Fold Change≥1.4), 4 vs. 0 Gy irradiation Genbank Fold Change P -Value Gene Symbol Description Accession Q9F8M7_CARHY (Q9F8M7) DTDP-glucose 4,6-dehydratase (Fragment), partial (9%) 6.70 0.017399678 THC2699065 [THC2719287] 5.53 0.003379195 BC013657 BC013657 Homo sapiens cDNA clone IMAGE:4152983, partial cds. [BC013657] 5.10 0.024641735 THC2750781 Ciliary dynein heavy chain 5 (Axonemal beta dynein heavy chain 5) (HL1). 4.07 0.04353262 DNAH5 [Source:Uniprot/SWISSPROT;Acc:Q8TE73] [ENST00000382416] 3.81 0.002855909 NM_145263 SPATA18 Homo sapiens spermatogenesis associated 18 homolog (rat) (SPATA18), mRNA [NM_145263] AA418814 zw01a02.s1 Soares_NhHMPu_S1 Homo sapiens cDNA clone IMAGE:767978 3', 3.69 0.03203913 AA418814 AA418814 mRNA sequence [AA418814] AL356953 leucine-rich repeat-containing G protein-coupled receptor 6 {Homo sapiens} (exp=0; 3.63 0.0277936 THC2705989 wgp=1; cg=0), partial (4%) [THC2752981] AA484677 ne64a07.s1 NCI_CGAP_Alv1 Homo sapiens cDNA clone IMAGE:909012, mRNA 3.63 0.027098073 AA484677 AA484677 sequence [AA484677] oe06h09.s1 NCI_CGAP_Ov2 Homo sapiens cDNA clone IMAGE:1385153, mRNA sequence 3.48 0.04468495 AA837799 AA837799 [AA837799] Homo sapiens hypothetical protein LOC340109, mRNA (cDNA clone IMAGE:5578073), partial 3.27 0.031178378 BC039509 LOC643401 cds. [BC039509] Homo sapiens Fas (TNF receptor superfamily, member 6) (FAS), transcript variant 1, mRNA 3.24 0.022156298 NM_000043 FAS [NM_000043] 3.20 0.021043295 A_32_P125056 BF803942 CM2-CI0135-021100-477-g08 CI0135 Homo sapiens cDNA, mRNA sequence 3.04 0.043389246 BF803942 BF803942 [BF803942] 3.03 0.002430239 NM_015920 RPS27L Homo sapiens ribosomal protein S27-like (RPS27L), mRNA [NM_015920] Homo sapiens tumor necrosis factor receptor superfamily, member 10c, decoy without an 2.98 0.021202829 NM_003841 TNFRSF10C intracellular domain (TNFRSF10C), mRNA [NM_003841] 2.97 0.03243901 AB002384 C6orf32 Homo sapiens mRNA for KIAA0386 gene, partial cds.
    [Show full text]
  • Genetic Testing Policy Number: PG0041 ADVANTAGE | ELITE | HMO Last Review: 04/11/2021
    Genetic Testing Policy Number: PG0041 ADVANTAGE | ELITE | HMO Last Review: 04/11/2021 INDIVIDUAL MARKETPLACE | PROMEDICA MEDICARE PLAN | PPO GUIDELINES This policy does not certify benefits or authorization of benefits, which is designated by each individual policyholder terms, conditions, exclusions and limitations contract. It does not constitute a contract or guarantee regarding coverage or reimbursement/payment. Paramount applies coding edits to all medical claims through coding logic software to evaluate the accuracy and adherence to accepted national standards. This medical policy is solely for guiding medical necessity and explaining correct procedure reporting used to assist in making coverage decisions and administering benefits. SCOPE X Professional X Facility DESCRIPTION A genetic test is the analysis of human DNA, RNA, chromosomes, proteins, or certain metabolites in order to detect alterations related to a heritable or acquired disorder. This can be accomplished by directly examining the DNA or RNA that makes up a gene (direct testing), looking at markers co-inherited with a disease-causing gene (linkage testing), assaying certain metabolites (biochemical testing), or examining the chromosomes (cytogenetic testing). Clinical genetic tests are those in which specimens are examined and results reported to the provider or patient for the purpose of diagnosis, prevention or treatment in the care of individual patients. Genetic testing is performed for a variety of intended uses: Diagnostic testing (to diagnose disease) Predictive
    [Show full text]
  • Impaired Autophagy Triggered by HDAC9 in Mesenchymal Stem Cells Accelerates Bone Mass Loss
    Impaired autophagy triggered by HDAC9 in mesenchymal stem cells accelerates bone mass loss Running title: HDAC9 impairs MSCs differentiation via autophagy. Zhang Liqiang1,2,4, Qi Meng1, 4, Chen Ji1,4，Zhao Jiangdong3, Li Liya2, Hu Jiachen1, Jin Yan1,2*, Liu Wenjia1,2* 1. State Key Laboratory of Military Stomatology& National Clinical Research Center for Oral Diseases&Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China. 2. Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi 710032, China. 3. The Key Laboratory of Aerospace Medicine, Ministry of Education, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China. 4. These authors contributed equally to this work. Correspondence Wenjia Liu & Yan Jin, Center for Tissue Engineering, Fourth Military Medical University, No. 145 West Changle Road, Xi’an, Shaanxi, China. Emails: [email protected] or [email protected]；[email protected]; Abstract Background: Bone mass loss in aging is linked with imbalanced lineage differentiation of bone marrow mesenchymal stem cells (BMMSCs). Recent studies have proved that histone deacetylases (HDACs) are regarded as key regulators of bone remodeling. However, HDACs involve in regulating BMMSCs bio-behaviors remain elusive. Here, we investigated ability of HDAC9 on modulation of autophagy and its significance in lineage differentiation of BMMSCs. Methods: The effects of HDAC9 on lineage differentiation of BMMSCs and autophagic signalling were assessed by various biochemical (Western blot and ChIP assay), morphological (TEM and confocal microscopy) and microCT assays. Results ： 16-month mice manifested obvious bone mass loss and marrow fat increase, accompanied with the decreased osteogenic differentiation and increased adipogenic differentiation of BMMSCs.
    [Show full text]
  • Transdifferentiation of Human Mesenchymal Stem Cells
    Transdifferentiation of Human Mesenchymal Stem Cells Dissertation zur Erlangung des naturwissenschaftlichen Doktorgrades der Julius-Maximilians-Universität Würzburg vorgelegt von Tatjana Schilling aus San Miguel de Tucuman, Argentinien Würzburg, 2007 Eingereicht am: Mitglieder der Promotionskommission: Vorsitzender: Prof. Dr. Martin J. Müller Gutachter: PD Dr. Norbert Schütze Gutachter: Prof. Dr. Georg Krohne Tag des Promotionskolloquiums: Doktorurkunde ausgehändigt am: Hiermit erkläre ich ehrenwörtlich, dass ich die vorliegende Dissertation selbstständig angefertigt und keine anderen als die von mir angegebenen Hilfsmittel und Quellen verwendet habe. Des Weiteren erkläre ich, dass diese Arbeit weder in gleicher noch in ähnlicher Form in einem Prüfungsverfahren vorgelegen hat und ich noch keinen Promotionsversuch unternommen habe. Gerbrunn, 4. Mai 2007 Tatjana Schilling Table of contents i Table of contents 1 Summary ........................................................................................................................ 1 1.1 Summary.................................................................................................................... 1 1.2 Zusammenfassung..................................................................................................... 2 2 Introduction.................................................................................................................... 4 2.1 Osteoporosis and the fatty degeneration of the bone marrow..................................... 4 2.2 Adipose and bone
    [Show full text]
  • Bioinformatics Analysis of the CDK2 Functions in Neuroblastoma
    MOLECULAR MEDICINE REPORTS 17: 3951-3959, 2018 Bioinformatics analysis of the CDK2 functions in neuroblastoma LIJUAN BO1*, BO WEI2*, ZHANFENG WANG2, DALIANG KONG3, ZHENG GAO2 and ZHUANG MIAO2 Departments of 1Infections, 2Neurosurgery and 3Orthopaedics, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China Received December 20, 2016; Accepted November 14, 2017 DOI: 10.3892/mmr.2017.8368 Abstract. The present study aimed to elucidate the poten- childhood cancer mortality (1,2). Despite intensive myeloabla- tial mechanism of cyclin-dependent kinase 2 (CDK2) in tive chemotherapy, survival rates for neuroblastoma have not neuroblastoma progression and to identify the candidate substantively improved; relapse is common and frequently genes associated with neuroblastoma with CDK2 silencing. leads to mortality (3,4). Like most human cancers, this child- The microarray data of GSE16480 were obtained from the hood cancer can be inherited; however, the genetic aetiology gene expression omnibus database. This dataset contained remains to be elucidated (3). Therefore, an improved under- 15 samples: Neuroblastoma cell line IMR32 transfected standing of the genetics and biology of neuroblastoma may with CDK2 shRNA at 0, 8, 24, 48 and 72 h (n=3 per group; contribute to further cancer therapies. total=15). Significant clusters associated with differen- In terms of genetics, neuroblastoma tumors from patients tially expressed genes (DEGs) were identified using fuzzy with aggressive phenotypes often exhibit significant MYCN C-Means algorithm in the Mfuzz package. Gene ontology and proto-oncogene, bHLH transcription factor (MYCN) amplifi- pathway enrichment analysis of DEGs in each cluster were cation and are strongly associated with a poor prognosis (5).
    [Show full text]
  • Oxidized Phospholipids Regulate Amino Acid Metabolism Through MTHFD2 to Facilitate Nucleotide Release in Endothelial Cells
    ARTICLE DOI: 10.1038/s41467-018-04602-0 OPEN Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells Juliane Hitzel1,2, Eunjee Lee3,4, Yi Zhang 3,5,Sofia Iris Bibli2,6, Xiaogang Li7, Sven Zukunft 2,6, Beatrice Pflüger1,2, Jiong Hu2,6, Christoph Schürmann1,2, Andrea Estefania Vasconez1,2, James A. Oo1,2, Adelheid Kratzer8,9, Sandeep Kumar 10, Flávia Rezende1,2, Ivana Josipovic1,2, Dominique Thomas11, Hector Giral8,9, Yannick Schreiber12, Gerd Geisslinger11,12, Christian Fork1,2, Xia Yang13, Fragiska Sigala14, Casey E. Romanoski15, Jens Kroll7, Hanjoong Jo 10, Ulf Landmesser8,9,16, Aldons J. Lusis17, 1234567890():,; Dmitry Namgaladze18, Ingrid Fleming2,6, Matthias S. Leisegang1,2, Jun Zhu 3,4 & Ralf P. Brandes1,2 Oxidized phospholipids (oxPAPC) induce endothelial dysfunction and atherosclerosis. Here we show that oxPAPC induce a gene network regulating serine-glycine metabolism with the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) as a cau- sal regulator using integrative network modeling and Bayesian network analysis in human aortic endothelial cells. The cluster is activated in human plaque material and by atherogenic lipo- proteins isolated from plasma of patients with coronary artery disease (CAD). Single nucleotide polymorphisms (SNPs) within the MTHFD2-controlled cluster associate with CAD. The MTHFD2-controlled cluster redirects metabolism to glycine synthesis to replenish purine nucleotides. Since endothelial cells secrete purines in response to oxPAPC, the MTHFD2- controlled response maintains endothelial ATP. Accordingly, MTHFD2-dependent glycine synthesis is a prerequisite for angiogenesis. Thus, we propose that endothelial cells undergo MTHFD2-mediated reprogramming toward serine-glycine and mitochondrial one-carbon metabolism to compensate for the loss of ATP in response to oxPAPC during atherosclerosis.
    [Show full text]
  • Characterizing the Roles of Exit Tunnel Residues in Ligand Binding
    CHARACTERIZING THE ROLES OF EXIT TUNNEL RESIDUES IN LIGAND BINDING AND CATALYSIS OF HISTONE DEACETYLASE-8 A Thesis Submitted to the Graduate Faculty of the North Dakota State University of Agriculture and Applied Science By Ruchi Gupta In Partial Fulfillment for the Degree of MASTER OF SCIENCE Major Department: Chemistry and Biochemistry March 2014 Fargo, North Dakota North Dakota State University Graduate School Title Characterizing the Roles of Exit Tunnel Residues in Ligand Binding and Catalysis of Histone Deacetylase-8 By Ruchi Gupta The Supervisory Committee certifies that this disquisition complies with North Dakota State University’s regulations and meets the accepted standards for the degree of MASTER OF SCIENCE SUPERVISORY COMMITTEE: Dr. D.K. Srivastava Chair Dr. Gregory Cook Dr. Stuart Haring Dr. Jane Schuh Approved: 03/26/2014 Gregory Cook Date Department Chair ABSTRACT Histone deacetylases are an important class of enzymes that catalyze the hydrolysis of acetyl-L-lysine side chains in histone and non-histone proteins to yield L-lysine and acetate, effecting the epigenetic regulation of gene expression. In addition to the active site pocket, the enzyme harbors an internal cavity for the release of acetate by-product. To probe the role of highly conserved amino acid residues lining this exit tunnel, site-directed alanine substitutions were made at tyrosine-18, tyrosine-20 and histidine-42 positions. These mutants were characterized by various biochemical and biophysical techniques to define the effect of mutations on ligand binding and catalysis of the enzyme. The mutations altered the catalytic activity of HDAC8 significantly. Y18A mutation dramatically impaired the structural-functional aspects of the enzymatic reaction.
    [Show full text]
  • The Key Role of DNA Methylation and Histone Acetylation in Epigenetics of Atherosclerosis
    J Lipid Atheroscler. 2020 Sep;9(3):419-434 Journal of https://doi.org/10.12997/jla.2020.9.3.419 Lipid and pISSN 2287-2892·eISSN 2288-2561 Atherosclerosis Review The Key Role of DNA Methylation and Histone Acetylation in Epigenetics of Atherosclerosis Han-Teo Lee ,1,2,* Sanghyeon Oh ,1,2,* Du Hyun Ro ,1,2,3,* Hyerin Yoo ,1,2 Yoo-Wook Kwon 4,5 1Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science, Seoul National University, Seoul, Korea 2Interdisciplinary Program in Stem Cell Biology, Graduate School of Medicine, Seoul National University, Seoul, Korea 3Department of Orthopedic Surgery, Seoul National University Hospital, Seoul, Korea 4Strategic Center of Cell and Bio Therapy for Heart, Diabetes & Cancer, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea Received: May 8, 2020 5Department of Medicine, College of Medicine, Seoul National University, Seoul, Korea Revised: Sep 14, 2020 Accepted: Sep 15, 2020 Correspondence to ABSTRACT Yoo-Wook Kwon Biomedical Research Institute, Seoul National Atherosclerosis, which is the most common chronic disease of the coronary artery, constitutes University Hospital, 103 Daehak-ro, Jongno- a vascular pathology induced by inflammation and plaque accumulation within arterial vessel gu, Seoul 03080, Korea. E-mail: [email protected] walls. Both DNA methylation and histone modifications are epigenetic changes relevant for atherosclerosis. Recent studies have shown that the DNA methylation and histone *Han-Teo Lee, Sanghyeon Oh and Du Hyun Ro modification systems are closely interrelated and mechanically dependent on each other. contributed equally to this work. Herein, we explore the functional linkage between these systems, with a particular emphasis Copyright © 2020 The Korean Society of Lipid on several recent findings suggesting that histone acetylation can help in targeting DNA and Atherosclerosis.
    [Show full text]
  • Role of Hdacs in Normal and Malignant Hematopoiesis Pan Wang1,2, Zi Wang1,2* and Jing Liu2*
    Wang et al. Molecular Cancer (2020) 19:5 https://doi.org/10.1186/s12943-019-1127-7 REVIEW Open Access Role of HDACs in normal and malignant hematopoiesis Pan Wang1,2, Zi Wang1,2* and Jing Liu2* Abstract Normal hematopoiesis requires the accurate orchestration of lineage-specific patterns of gene expression at each stage of development, and epigenetic regulators play a vital role. Disordered epigenetic regulation has emerged as a key mechanism contributing to hematological malignancies. Histone deacetylases (HDACs) are a series of key transcriptional cofactors that regulate gene expression by deacetylation of lysine residues on histone and nonhistone proteins. In normal hematopoiesis, HDACs are widely involved in the development of various lineages. Their functions involve stemness maintenance, lineage commitment determination, cell differentiation and proliferation, etc. Deregulation of HDACs by abnormal expression or activity and oncogenic HDAC-containing transcriptional complexes are involved in hematological malignancies. Currently, HDAC family members are attractive targets for drug design, and a variety of HDAC-based combination strategies have been developed for the treatment of hematological malignancies. Drug resistance and limited therapeutic efficacy are key issues that hinder the clinical applications of HDAC inhibitors (HDACis). In this review, we summarize the current knowledge of how HDACs and HDAC-containing complexes function in normal hematopoiesis and highlight the etiology of HDACs in hematological malignancies. Moreover, the implication and drug resistance of HDACis are also discussed. This review presents an overview of the physiology and pathology of HDACs in the blood system. Keywords: Histone deacetylases, Hematopoiesis, Hematological malignancy, HDAC inhibitor, Drug resistance Introduction nuclear localization [5, 6].
    [Show full text]